rs61749896

Variant names:

• chr13-102861622-G-A
• rs61749896
• NM_000123.4:c.788G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-102861622-G-A
• chr13-102861622-G-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001204425.2(BIVM-ERCC5):​c.2150G>A​(p.Arg717Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000673 in 1,614,000 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (2 hom.)
• Consequence: BIVM-ERCC5 NM_001204425.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4 O:1
• Conservation: PhyloP100: 2.09
• Publications: 8 publications found

Genes affected

ERCC5 (HGNC:3437): (ERCC excision repair 5, endonuclease) This gene encodes a single-strand specific DNA endonuclease that makes the 3' incision in DNA excision repair following UV-induced damage. The protein may also function in other cellular processes, including RNA polymerase II transcription, and transcription-coupled DNA repair. Mutations in this gene cause xeroderma pigmentosum complementation group G (XP-G), which is also referred to as xeroderma pigmentosum VII (XP7), a skin disorder characterized by hypersensitivity to UV light and increased susceptibility for skin cancer development following UV exposure. Some patients also develop Cockayne syndrome, which is characterized by severe growth defects, cognitive disability, and cachexia. Read-through transcription exists between this gene and the neighboring upstream BIVM (basic, immunoglobulin-like variable motif containing) gene. [provided by RefSeq, Feb 2011]

BIVM-ERCC5 (HGNC:43690): (BIVM-ERCC5 readthrough) This locus represents naturally occurring read-through transcription between the neighboring BIVM (basic, immunoglobulin-like variable motif containing) and ERCC5 (excision repair cross-complementing rodent repair deficiency, complementation group 5) genes on chromosome 13. The read-through transcript encodes a fusion protein that shares sequence identity with the products of each individual gene. [provided by RefSeq, Feb 2011]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006557137).
• BP6: Variant 13-102861622-G-A is Benign according to our data. Variant chr13-102861622-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134185.
• BS2: High Homozygotes in GnomAdExome4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001204425.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC5	NM_000123.4	MANE Select	c.788G>A	p.Arg263Gln	missense	Exon 7 of 15	NP_000114.3
	BIVM-ERCC5	NM_001204425.2		c.2150G>A	p.Arg717Gln	missense	Exon 15 of 23	NP_001191354.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC5	ENST00000652225.2	MANE Select	c.788G>A	p.Arg263Gln	missense	Exon 7 of 15	ENSP00000498881.2
	BIVM-ERCC5	ENST00000639435.1	TSL:5	c.2150G>A	p.Arg717Gln	missense	Exon 17 of 25	ENSP00000491742.1
	BIVM-ERCC5	ENST00000639132.1	TSL:5	c.1463G>A	p.Arg488Gln	missense	Exon 16 of 24	ENSP00000492684.1

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000593 AC: 149 AN: 251382 AF XY: 0.000493

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000783

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000683 AC: 998 AN: 1461850 Hom.: 2 Cov.: 31 AF XY: 0.000622 AC XY: 452 AN XY: 727224

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.00112 AC: 50 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000262 AC: 14 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000811 AC: 902 AN: 1111992

Other (OTH) AF: 0.000381 AC: 23 AN: 60394

GnomAD4 genome AF: 0.000585 AC: 89 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35 AN XY: 74330

African (AFR) AF: 0.000169 AC: 7 AN: 41428

American (AMR) AF: 0.000327 AC: 5 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00107 AC: 73 AN: 68038

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000587 Hom.: 2

Bravo AF: 0.000631

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000346 AC: 42

EpiCase AF: 0.00104

EpiControl AF: 0.000474

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	1	Xeroderma pigmentosum, group G (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	15
DANN	Benign	0.52
DEOGEN2	Benign	0.043	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.2	N
PhyloP100		2.1
PROVEAN	Benign	1.7	N
REVEL	Benign	0.026
Sift	Benign	1.0	T
Sift4G	Benign	0.78	T
Polyphen		0.011	B
Vest4		0.046
MVP		0.11
MPC		0.13
ClinPred		0.0097	T
GERP RS		1.8
Varity_R		0.019
gMVP		0.037
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61749896; hg19: chr13-103513972; COSMIC: COSV63245188; COSMIC: COSV63245188;